Research - Vitamin E
A Prospective Study of Serum Vitamin E and 28-Year Risk of Lung Cancer
Jiaqi Huang Stephanie J Weinstein Kai Yu Satu Männistö Demetrius Albanes
Epidemiologic data are inconsistent regarding the vitamin E-lung cancer association, and no study has examined serologic changes in vitamin E status in relation to subsequent risk.
In a cohort of 22,781 male smokers in the ATBC Study, we ascertained 3,184 lung cancer cases during up to 28 years of observation. Cox proportional hazards models examined whether higher serum alpha-tocopherol concentrations at baseline, 3 years, or the interval change were associated with lower lung cancer risk. All statistical tests were two-sided.
After adjustment for age, body mass index, smoking intensity and duration, serum total cholesterol, and trial intervention group, we found lower lung cancer risk in men with high baseline alpha-tocopherol (5th quintile (Q5) vs Q1, hazard ratio (HR)=0.76, 95%CI =0.66 to 0.87; Ptrend<0.001). A similar reduction in risk was seen for serum alpha-tocopherol at 3 years (Q5 vs Q1, HR = 0.78, 95%CI =0.67 to 0.91; Ptrend=0.004). The inverse risk association appeared stronger for younger men and those having smoked fewer years, but was similar across trial intervention groups. We also found reduced risk among un-supplemented men with a lower serum alpha-tocopherol at baseline who had greater increases in concentrations at 3 years (3rd tertile vs 1st tertile of serum alpha-tocopherol change, HR = 0.74, 95% CI = 0.59 to 0.91, P=0.005).
Higher vitamin E status, as measured by serum alpha-tocopherol concentration, as well as repletion of a low vitamin E state, was related to decreased lung cancer risk during a 28-year period. Our findings provide evidence supporting the importance of adequate physiological vitamin E status for lung cancer risk reduction.
Source : Journal of the National Cancer Institute
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Daily Consumption of Oregon Hazelnuts Affects α-Tocopherol Status in Healthy Older Adults: A Pre-Post Intervention Study
lexander J Michels , Scott W Leonard, Sandra L Uesugi, Gerd Bobe, Balz Frei, and Maret G Traber
Background: Inadequate vitamin E and magnesium intakes are of concern for older adults owing to the associated incidence of age-related diseases.
Objective: This study was designed to determine the extent to which a 16-wk intervention with hazelnuts alters vitamin E and magnesium status in a group of older men and women, and used a pre-post intervention design without a control group to adjust for temporal changes.
Methods: Participants (n = 32 including 22 women; mean ± SD age: 63 ± 6 y) consumed hazelnuts (∼57 g/d) for 16 wk. Blood and urine samples and anthropomorphic measures were taken at the start and end of the intervention to determine plasma concentrations of α-tocopherol and serum concentrations of magnesium, lipids, glucose, insulin, and high-sensitivity C-reactive protein along with urinary vitamin E metabolites; several other micronutrients were measured by a lymphocyte proliferation assay. There were 3 primary endpoints, calculated as the mean changes in measurements between baseline and the end of the 16-wk intervention for 1) plasma α-tocopherol, 2) urinary α-carboxyethyl hydroxychromanol (α-CEHC; an α-tocopherol metabolite), and 3) serum magnesium.
esults: Hazelnut consumption increased concentrations of the urinary α-tocopherol metabolite α-CEHC (mean ± SD: 0.84 ± 0.45 to 1.14 ± 0.50 µmol/g creatinine; P = 0.0006). In addition, hazelnut consumption increased serum concentrations of magnesium (+2.1%, P = 0.05), decreased concentrations of fasting glucose (−3.4%, P = 0.03) and LDL cholesterol (−6.0%, P = 0.02), and decreased total:HDL cholesterol ratios (−4.5%, P = 0.009). No significant changes were observed in blood pressure, lymphocyte proliferation assays, and serum concentrations of insulin, highsensitivity C-reactive protein, triglyceride, α-tocopherol, or HDL cholesterol.
Conclusions: Consuming hazelnuts improves a biomarker of vitamin E status in older adults. Vitamin E is a shortfall micronutrient, as identified by the Dietary Guidelines for Americans 2015–2020, which frequently is consumed at levels less than the Estimated Average Requirement of 12 mg/d; thus, hazelnuts should be considered as part of a healthy dietary pattern
Source : The Journal of Nutrition
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Positive Association of Vitamin E Supplementation with Hemoglobin Levels in Mildly Anemic Healthy Pakistani Adults
Tanveer JilaniRelated information
Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, Pakistan
, Iqbal AzamRelated information
Department of Community Health Sciences, Aga Khan University, Karachi, Pakistan
, Bushra MoizRelated information
Department of Pathology and Microbiology, Aga Khan University, Karachi, Pakistan
, Naseema MehboobaliRelated information
Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, Pakistan
, and Mohammad Perwaiz Iqba
Background: Hemoglobin levels slightly below the lower limit of normal are common in adults in the general population in developing countries. A few human studies have suggested the use of antioxidant vitamins in the correction of mild anemia. The objective of the present study was to investigate the association of vitamin E supplementation in mildly anemic healthy adults with post-supplemental blood hemoglobin levels in the general population of Karachi, Pakistan.
Method: In a single-blinded and placebo-controlled randomized trial, 124 mildly anemic subjects from the General Practitioners’ Clinics and personnel of the Aga Khan University were randomized into intervention (n = 82) and control (n = 42) group. In the intervention group, each subject was given vitamin E (400 mg) everyday for a period of three months, while control group subjects received a placebo. Eighty six subjects completed the trial. Fasting venous blood was collected at baseline and after three months of supplementation. Hemoglobin levels and serum/plasma concentrations of vitamin E, vitamin B12, folate, ferritin, serum transferrin receptor (sTfR), glucose, total cholesterol, triglycerides, LDL-cholesterol, HDL-cholesterol, creatinine, total-antioxidant-status and erythropoietin were measured and analyzed using repeated measures ANOVA and multiple linear regression.
Results: The adjusted regression coefficients (β) and standard error [SE(β)] of the significant predictors of post-supplemental hemoglobin levels were serum concentration of vitamin E (0.983[0.095]), gender (- 0.656[0.244]), sTfR (- 0.06[0.02]) and baseline hemoglobin levels (0.768[0.077]).
Conclusion: The study showed a positive association between vitamin E supplementation and enhanced hemoglobin levels in mildly anemic adults.
Source : Intl Journal for Vitamin and Nutrition Research
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Vitamin E Analogs as Radiation Response Modifiers
Pankaj K. Singh and Sunil Krishnan
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
The potentially life-threatening effects of total body ionizing radiation exposure have been known for more than a century. Despite considerable advances in our understanding of the effects of radiation over the past six decades, efforts to identify effective radiation countermeasures for use in case of a radiological/nuclear emergency have been largely unsuccessful. Vitamin E is known to have antioxidant properties capable of scavenging free radicals, which have critical roles in radiation injuries. Tocopherols and tocotrienols, vitamin E analogs together known as tocols, have shown promise as radioprotectors. Although the pivotal mechanisms of action of tocols have long been thought to be their antioxidant properties and free radical scavenging activities, other alternative mechanisms have been proposed to drive their activity as radioprotectors. Here we provide a brief overview of the effects of ionizing radiation, the mechanistic mediators of radiation-induced damage, and the need for radiation countermeasures. We further outline the role for, efficacy of, and mechanisms of action of tocols as radioprotectors, and we compare and contrast their efficacy and mode of action with that of another well-studied chemical radioprotector, amifostine.
....Taken together, these promising findings of preclinical radioprotective activity of newer tocols beyond α-tocopherol warrant continued evaluation of their pharmacokinetics, bioavailability, pharmacodynamics, tolerability, and efficacy in large animal models. A greater understanding of mechanisms of action may facilitate adoption of newer strategies such as alpha-tocopherol succinate-mobilized cellular therapy as a bridge to recovery of innate hematopoietic cells after radiation injury or design of synthetic analogs based on analysis of structure-function relationships critical for specific activity. Collectively, recent advances in our knowledge of vitamin E derivatives provide a framework for the advancement of such agents as viable radiation countermeasures
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Additive Antinociceptive Effects of a Combination of Vitamin C and Vitamin E after Peripheral Nerve Injury
- Ruirui Lu,
- Wiebke Kallenborn-Gerhardt,
- Gerd Geisslinger,
- Achim Schmidtko
Accumulating evidence indicates that increased generation of reactive oxygen species (ROS) contributes to the development of exaggerated pain hypersensitivity during persistent pain. In the present study, we investigated the antinociceptive efficacy of the antioxidants vitamin C and vitamin E in mouse models of inflammatory and neuropathic pain. We show that systemic administration of a combination of vitamins C and E inhibited the early behavioral responses to formalin injection and the neuropathic pain behavior after peripheral nerve injury, but not the inflammatory pain behavior induced by Complete Freund's Adjuvant. In contrast, vitamin C or vitamin E given alone failed to affect the nociceptive behavior in all tested models. The attenuated neuropathic pain behavior induced by the vitamin C and E combination was paralleled by a reduced p38 phosphorylation in the spinal cord and in dorsal root ganglia, and was also observed after intrathecal injection of the vitamins. Moreover, the vitamin C and E combination ameliorated the allodynia induced by an intrathecally delivered ROS donor. Our results suggest that administration of vitamins C and E in combination may exert synergistic antinociceptive effects, and further indicate that ROS essentially contribute to nociceptive processing in special pain states.
Source : PLOSone
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Antioxidants prevent memory deficits provoked by chronic variable stress in rats.
Tagliari B1, Scherer EB, Machado FR, Ferreira AG, Dalmaz C, Wyse AT.Author information
Learning and memory deficits occur in depression and other stress related disorders. Although the pathogenesis of cognitive impairment after stress has not been fully elucidated, factors such as oxidative stress and neurotrophins are thought to play possible roles. Here we investigated the effect of treatment with vitamin E (40 mg/kg) and vitamin C (100 mg/kg) on the effects elicited by chronic variable stress on rat performance in Morris water maze. Brain-derived neurotrophic factor (BDNF) immunocontent was also evaluated in hippocampus of rats. Sixty-day old Wistar rats were submitted to different stressors for 40 days (stressed group). Half of stressed group received administration of vitamins once a day, during the period of stress. Chronically stressed rats presented a marked decrease in reference memory in the water maze task as well as a reduced efficiency to find the platform in the working memory task. Rats treated with vitamins E and C had part of the above effects prevented, suggesting the participation of oxidative stress in such effects. The BDNF levels were not altered in hippocampus of stressed group when compared to controls. Our findings lend support to a novel therapeutic strategy, associated with these vitamins, to the cognitive dysfunction observed in depression and other stress related diseases.
Source : Neurochem Res
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The Role of Phytonutrients in Skin Health
Julie A. Evans and Elizabeth J. Johnson*
Photodamage is known to occur in skin with exposure to sunlight, specifically ultraviolet (UV) radiation. Such damage includes inflammation, oxidative stress, breakdown of the extracellular matrix, and development of cancer in the skin. Sun exposure is considered to be one of the most important risk factors for both nonmelanoma and melanoma skin cancers. Many phytonutrients have shown promise as photoprotectants in clinical, animal and cell culture studies. In part, the actions of these phytonutrients are thought to be through their actions as antioxidants. In regard to skin health, phytonutrients of interest include vitamin E, certain flavonoids, and the carotenoids, β-carotene, lycopene and lutein.
Source : Journal Nutrients
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Not Any Old Vitamin E Prevents, Reverses Lung Cancer
The media has given an astounding amount of attention to a recent study that found vitamin E may increase tumor progression, and accelerate lung cancer, in mice.1
Unfortunately, they are only adding to the major confusion surrounding vitamin E, which is a potent antioxidant and immune-system booster provided it's consumed in the correct form.
Your body can easily distinguish between natural and synthetic vitamins, the latter of which may not only be less effective but may also have unintended negative consequences in your body. This is often the case with vitamin E, the synthetic form of which was used in the recent media-hyped lung cancer study.
Synthetic Vitamin E May Cause Lung Cancer This is what the media headlines should have read, but very few media outlets have made the distinction that the study used DL-a-tocopheryl acetate, a synthetic form of vitamin E.
As noted by GreenMedInfo, synthetic vitamin E is a "byproduct of a petrochemical-dependent manufacturing process and may have adverse endocrine-disrupting activities."2
It is this synthetic form of vitamin E that has previously been linked to increased risks of prostate cancer, along with other ill effects such as a hemorrhagic stroke and pneumonia.3 The Toxicology Data Network also lists numerous health problems related to synthetic vitamin E at various dosages.4
Many are simply not aware that the term "vitamin E" actually refers to a family of at least eight fat-soluble antioxidant compounds, divided into two groups of molecules:
- Tocopherols (which are considered the "true" vitamin E)
The problem, as was once again highlighted with the aforementioned lung cancer study, is the vitamin E most often referred to in research (and sold in most stores) is the synthetic form of the vitamin, which will not provide your body with the benefits that natural full-spectrum vitamin E will.
The featured lung cancer study, for instance, not only used synthetic vitamin E (tocopheryl) but also neglected to include any tocotrienols, which have previously been shown to kill cancer stem cells, the most malignant of all cells with a tumor.5 As noted by Dr. Andrew Saul, the study was set up to fail:6
"Synthetic vitamin E was selected. It did not work. Natural vitamin E was not used. Tocotrienols were not used. I challenge any scientist or journalist to try to explain these omissions away."
Natural Vitamin E May Prevent Cancer, Benefit Alzheimer's, and More If the lung cancer study had used natural vitamin E for its research, they may have gotten entirely different results, as natural vitamin E has shown many cancer-fighting properties. For instance:
- 300 IUs of natural vitamin E per day may reduce lung cancer risk by 61 percent7
- Gamma-tocotrienol, a cofactor found in natural vitamin E preparations, may decrease prostate tumor formation by 75 percent8
- Gamma-tocotrienol also fights existing prostate cancer tumors and may inhibit growth in human breast cancer cells9
- Relieving the majority of symptoms associated with nonalcoholic steatohepatitis (NASH), a common obesity-related fatty liver disease.
- Helping to delay loss of cognitive function, such as planning and organizing, in Alzheimer's patients.10 (This study actually used synthetic alpha-tocopherol that was not balanced with tocotrienols or any of the other tocopherols — beta, gamma, and delta. Chances are the benefits would have been even greater if the natural form was used.)
- Lowering your risk of age-related macular degeneration (AMD), a leading cause of vision loss in the elderly.11
- Boosting the improvements in blood vessel function that occur when a smoker quits smoking.12
- Natural vitamin E is always listed as the "d-" form (d-alpha-tocopherol, d-beta-tocopherol, etc.)
- Synthetic vitamin E is listed as "dl-" forms
Are You Getting Enough Vitamin E From Your Diet? According to the National Institutes of Health:13 "The diets of most Americans provide less than the recommended amounts of vitamin E." That recommended amount is just 22 IUs of vitamin E daily, an amount that Dr. Evan Shute, a physician recognized for his 30-plus years of work with vitamin E, believes is still far too low. He suggests average healthy women should have 400 IUs a day while men should have 600 IUs daily.
The best way to ensure that your body is getting the full spectrum of vitamin E, in a form your body can beneficially use, is to make smart dietary choices. Tocopherol and its subgroups are found in certain nuts and green leafy vegetables, for instance. Sources of tocotrienols include palm oil, rice bran, and barley oils.
While vitamin E is also found in vegetable oils, these are many reasons not to include these in your diet, including the facts that they will become rancid and oxidized when heated and typically are made from genetically engineered crops. So there are actually relatively few healthful dietary sources of vitamin E, which is why a natural supplement may be necessary for some. If you're interested in increasing your dietary sources of vitamin E, try eating more:
- Nuts, such as hazelnuts, almonds, walnuts, and pecans
- Green vegetables, such as spinach and broccoli
- Exposure to radon
- Exposure to asbestos
- Air pollution
- Exposure to other chemicals
- Increasing age
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Intake and serum concentrations of α-tocopherol in relation to fractures in elderly women and men: 2 cohort studies1,2,3
Karl Michaëlsson,Alicja Wolk, Liisa Byberg, Johan Ärnlöv, Håkan Melhus
1From the Department of Surgical Sciences, Orthopedics, Uppsala University, Uppsala, Sweden (KM and LB); the Division of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (AW); the School of Health and Social Studies, Dalarna University, Falun, Sweden (JÄ); the Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, Sweden (JÄ); and the Department of Medical Sciences, Clinical Pharmacology, Uppsala University, Uppsala, Sweden (HM).
Abstract Background: A reduction in the formation of free radicals and oxidative stress might reduce the rate of bone loss and muscle wasting.
Objective: The objective was to determine whether α-tocopherol intake or serum concentrations are associated with fracture risk in older women and men.
Design: Two cohort studies, the Swedish Mammography Cohort (SMC; n = 61,433 women) and the Uppsala Longitudinal Study of Adult Men (ULSAM; n = 1138 men), were used.
Results: During 19 y of follow-up, 14,738 women in the SMC experienced a first fracture at any site (3871 hip fractures). A higher hip fracture rate was observed with lower intakes of α-tocopherol. Compared with the highest quintile of intake, the lowest quintile had a multivariable-adjusted HR of 1.86 (95% CI: 1.67, 2.06). The HR of any fracture was 1.20 (95% CI: 1.14, 1.28). α-Tocopherol–containing supplement use was associated with a reduced rate of hip fracture (HR: 0.78; 95% CI: 0.65, 0.93) and any fracture (HR: 0.86; 95% CI: 0.78, 0.94). Compared with the highest quintile of α-tocopherol intake in ULSAM (follow-up: 12 y), lower intakes (quintiles 1–4) were associated with a higher rate of hip fracture (HR: 3.33; 95% CI: 1.43, 7.76) and any fracture (HR: 1.84; 95% CI: 1.18, 2.88). The HR for hip fracture in men for each 1-SD decrease in serum α-tocopherol was 1.58 (95% CI: 1.13, 2.22) and for any fracture was 1.23 (95% CI: 1.02, 1.48).
Conclusion: Low intakes and low serum concentrations of α-tocopherol are associated with an increased rate of fracture in elderly women and men.
Source : American Journal of Clinical Nutrition
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Association of vitamin E and C supplement use with cognitive function and dementia in elderly men
- K.H. Masaki, MD,
- K.G. Losonczy, MA,
- G. Izmirlian, PhD,
- D.J. Foley, MS,
- G.W. Ross, MD,
- H. Petrovitch, MD,
- R. Havlik, MD and
- L.R. White, MD
Objective: To determine whether use of vitamin E and C supplements protects against subsequent development of dementia and poor cognitive functioning.
Methods: The Honolulu–Asia Aging Study is a longitudinal study of Japanese-American men living in Hawaii. Data for this study were obtained from a subsample of the cohort interviewed in 1982, and from the entire cohort from a mailed questionnaire in 1988 and the dementia prevalence survey in 1991 to 1993. The subjects included 3,385 men, age 71 to 93 years, whose use of vitamin E and C supplements had been ascertained previously. Cognitive performance was assessed with the Cognitive Abilities Screening Instrument, and subjects were stratified into four groups: low, low normal, mid normal, and high normal. For the dementia analyses, subjects were divided into five mutually exclusive groups: AD (n = 47), vascular dementia (n = 35), mixed/other types of dementia (n = 50), low cognitive test scorers without diagnosed dementia (n = 254), and cognitively intact (n = 2,999; reference).
Results: In a multivariate model controlling for other factors, a significant protective effect was found for vascular dementia in men who had reported taking both vitamin E and C supplements in 1988 (odds ratio [OR], 0.12; 95% CI, 0.02 to 0.88). They were also protected against mixed/other dementia (OR, 0.31; 95% CI, 0.11 to 0.89). No protective effect was found for Alzheimer’s dementia (OR, 1.81; 95% CI, 0.91 to 3.62). Among those without dementia, use of either vitamin E or C supplements alone in 1988 was associated significantly with better cognitive test performance at the 1991 to 1993 examination (OR, 1.25; 95% CI, 1.04 to 1.50), and use of both vitamin E and C together had borderline significance (OR, 1.18; 95% CI, 0.995 to 1.39).
Conclusions: These results suggest that vitamin E and C supplements may protect against vascular dementia and may improve cognitive function in late life.
Source : Journal Neurology
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Quit Smoking? Vitamin E May Give Extra Boost to Heart Health
Taking a specific form of a vitamin E supplement can accelerate the health benefits that occur when people quit smoking, new research suggests.In the small study, improvement in blood vessel function associated with the added vitamin E potentially translates into an estimated 19 percent greater drop in future risk for cardiovascular disease.
Smokers were recruited to participate in a study to quit smoking for seven days, with blood markers of inflammation and blood vessel function measured before and after the trial. After seven days of not smoking, participants saw an increase in their vascular function by an average of 2.8 percent. Those who quit smoking and also took the gamma-tocopherol form of vitamin E showed a 1.5 percent additional improvement in vascular function.
While these changes in vascular function may appear to be small, previous large-scale studies suggest that every 1 percent increase in vascular function – or improvement in the blood vessel’s ability to dilate – translates into a 13 percent drop in risk of developing heart disease later in life.
“This is a very short-term study that shows very promising effects,” said Richard Bruno, associate professor of human nutrition at The Ohio State University and senior author of the study.
“The underlying rationale is that we know it takes many years before the risk for cardiovascular disease of a former smoker matches that of a nonsmoker. We hope to develop a therapy to combine with smoking cessation that could accelerate the restoration of vascular function and reduce cardiovascular risk.”
The research was presented Tuesday (4/23) at the annual Experimental Biology meeting in Boston.
The supplement in the study is not the same as the average vitamin E available on most store shelves. Vitamin E occurs in eight forms based on their chemical structure, and the most well-known form belongs to a variety called tocopherols. In this study, researchers tested the effects of the gamma-tocopherol form. The most common form of vitamin E, and the one for which humans have a dietary requirement, is alpha-tocopherol.
Though taking gamma-tocopherol is safe, Bruno noted that longer-term studies with more participants would be required to nail down specific dietary recommendations related to smoking cessation.
A total of 30 smokers in their 20s who had smoked at least half a pack per day for a year participated in the study. All participants stopped smoking, and 16 received 500 milligrams daily of gamma-tocopherol while 14 received a placebo.
In addition to taking blood samples, researchers measured vascular function by obtaining ultrasound images of an artery in the upper arm as the vessel responded to a surge of blood flow after circulation in the arm was stopped for five minutes.
The quality of vascular function is defined by the artery’s ability to dilate in response to the surge of blood – more dilation suggests the vessel has appropriate responses to changes in blood flow.
“Greater dilatory response is an indicator of vascular health. People with a long history of smoking tend to have low vasodilatory responses,” Bruno said.
Participants who took the supplements showed greater improvements in vascular function and also had lower levels of two inflammation-related proteins in their blood than did participants who received a placebo.
Bruno said the lower levels of those two proteins in the supplemented participants’ blood suggest that the gamma-tocopherol form of vitamin E restores vascular function at least in part by lowering inflammation.
Gamma-tocopherol is abundant in the American diet, but is difficult to obtain from low-calorie sources. Food sources include soybean, canola and some other vegetable oils, and certain nuts such as pistachios, pecans, cashews and peanuts. Supplements that are rich in gamma-tocopherol can be found in specialty stores.
Source : Newswise
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Study Shows How Vitamin E Can Help Prevent Cancer
COLUMBUS, Ohio – Researchers have identified an elusive anti-cancer property of vitamin E that has long been presumed to exist, but difficult to find.
Many animal studies have suggested that vitamin E could prevent cancer, but human clinical trials following up on those findings have not shown the same benefits.
In this new work, researchers showed in prostate cancer cells that one form of vitamin E inhibits the activation of an enzyme that is essential for cancer cell survival. The loss of the enzyme, called Akt, led to tumor cell death. The vitamin had no negative effect on normal cells.
“This is the first demonstration of a unique mechanism of how vitamin E can have some benefit in terms of cancer prevention and treatment,” said lead author Ching-Shih Chen, professor of medicinal chemistry and pharmacognosy at The Ohio State University and an investigator in Ohio State’s Comprehensive Cancer Center.
The study appears in the March 19, 2013, issue of the journal Science Signaling.
Chen cautioned that taking a typical vitamin E supplement won’t offer this benefit for at least two reasons: The most affordable supplements are synthetic and based predominantly on a form of the vitamin that did not fight cancer as effectively in this study, and the human body can’t absorb the high doses that appear to be required to achieve the anti-cancer effect.
“Our goal is to develop a safe pill at the right dose that people could take every day for cancer prevention. It takes time to optimize the formulation and the dose,” he said.
Chen has filed an invention disclosure with the university, and Ohio State has filed a patent application for the agent.
Vitamin E occurs in numerous forms based on their chemical structure, and the most commonly known form belongs to a variety called tocopherols. In this study, researchers showed that, of the tocopherols tested, the gamma form of tocopherol was the most potent anti-cancer form of the vitamin.
The scientists manipulated the structure of that vitamin E molecule and found that the effectiveness of this new agent they created was 20-fold higher than the vitamin itself in cells. In experiments in mice, this agent reduced the size of prostate cancer tumors.
These findings suggest that an agent based on the chemical structure of one form of vitamin E could help prevent and treat numerous types of cancer – particularly those associated with a mutation in the PTEN gene, a fairly common cancer-related genetic defect that keeps Akt active.
The researchers began the work with both alpha and gamma forms of the vitamin E molecule. Both inhibited the enzyme called Akt in very targeted ways, but the gamma structure emerged as the more powerful form of the vitamin.
In effect, the vitamin halted Akt activation by attracting Akt and another protein, called PHLPP1, to the same region of a cell where the vitamin was absorbed: the fat-rich cell membrane. PHLPP1, a tumor suppressor, then launched a chemical reaction that inactivated Akt, rendering it unable to keep cancer cells alive.
“This is a new finding. We have been taking vitamin E for years but nobody really knew about this particular anti-cancer mechanism,” Chen said.
The gamma form was most effective because its chemical shape allowed it to attach to Akt in the most precise way to shut off the enzyme.
Because of how the various molecules interacted on the cell membrane, the scientists predicted that shortening a string of chemical groups dangling from the main body, or head group, of the gamma-tocopherol molecule would make those relationships even stronger. They lopped off about 60 percent of this side chain and tested the effects of the new agent in the prostate cancer cells.
“By reducing two-thirds of the chain, the molecule had a 20 times more potent anti-tumor effect, while retaining the integrity of vitamin E’s head group,” Chen said. This manipulation enhanced the anti-tumor potency of the molecule by changing its interaction with the cell membrane, so that the head group was more accessible to Akt and PHLPP1.
When mice with tumors created by these two prostate cancer cell lines were inSource : jected with the agent, the treatment suppressed tumor growth when compared to a placebo, which had no effect on tumor size. Chemical analysis of the treated tumors showed that the Akt enzyme signal was suppressed, confirming the effects were the same in animals as they had been in cell cultures.
The animal study also suggested the experimental agent was not toxic. Chen’s lab is continuing to work on improvements to the molecule.
Source : Ohio State University
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Vitamin E and Skin Health
Vitamin E is a fat-soluble antioxidant that is essential for the maintenance of healthy skin. Naturally occurring vitamin E is not a single compound; instead, vitamin E is a group of molecules with related structures, some of which may have unique properties in skin. Vitamin E is also found as vitamin E conjugates that increase stability but require cellular metabolism for activation. Vitamin E is normally provided to the skin through the sebum. Topical application can also supply the skin with vitamin E and may provide specific vitamin E forms that are not available from the diet. As an antioxidant, vitamin E primarily reacts with reactive oxygen species. In addition, vitamin E can also absorb the energy from ultraviolet (UV) light. Thus, it plays important roles in photoprotection, preventing UV-induced free radical damage to skin. Vitamin E may also have related anti-inflammatory roles in the skin. Other roles of vitamin E in the skin are poorly understood because research is limited. This article discusses the roles of vitamin E in the skin and summarizes the current knowledge about vitamin E in skin health.
Forms of Vitamin E
The term “vitamin E” does not refer to a single molecule but to two classes of molecules with similar structures and antioxidant properties, comprising a family of eight substances. Tocopherols are the most abundant form of vitamin E in the body, consisting of four different forms (alpha-, beta-, gamma-, and delta-tocopherol). Tocotrienols, which are found in the body to a lesser extent, also exist in four different forms (alpha-, beta-, gamma-, and delta-tocotrienol). Although tocopherols and tocotrienols are available from the diet, alpha-tocopherol is the primary form of vitamin E found and maintained in the body, due to the specificity of a transport protein for alpha-tocopherol (see the separate article on Vitamin E).
Naturally occurring vitamin E is usually labeled as “natural” or “d” vitamin E, while synthetic vitamin E is a mixture of eight isomeric forms, usually labeled “all-rac” or “dl.” Tocopherols and tocotrienols are also available as ester derivatives that increase molecular stability upon exposure to heat, light, and air. Conjugated vitamin E molecules are typically used in dietary supplements; the esterified molecule is removed by cellular metabolism in the intestine. However, metabolism of vitamin E conjugates in skin is low; therefore, the availability of unesterified or “free” vitamin E from cutaneous application of conjugates may be limited (see Topical Application below).
Content and Availability
Vitamin E is the most abundant lipophilic antioxidant found in human skin (1, 2). In humans, levels of vitamin E in the epidermis are higher than the dermis (1). Although the predominant form of vitamin E in skin of unsupplemented individuals is alpha-tocopherol, skin may also contain measurable amounts of gamma-tocopherol (3) and other diet-derived tocopherols and tocotrienols (4).
Vitamin E first accumulates in the sebaceous glands before it is delivered to the skin surface through sebum (5, 6). Following oral ingestion, it takes at least seven days before the vitamin E content of sebum is altered (5, 7). There are no transport proteins specific for vitamin E in the skin. Sebum is secreted to the surface of the stratum corneum, where it concentrates in the lipid-rich extracellular matrix of this layer (3). Due to its lipophilic nature, vitamin E can also penetrate into all underlying layers of skin (8). Skin vitamin E levels are higher in individuals with increased sebum production, as well as in skin types that naturally produce more sebum (e.g., “oily’ skin on the face vs. drier skin on the arm) (1, 8).
Exposures to UV light (3, 9, 10) or ozone (6, 11, 12) lower the vitamin E content in skin, primarily in the stratum corneum. Vitamin E concentrations in the human epidermis also decline with age1. Since epidermal structure changes with age (13), this may be due to increased UV penetration of this layer.
Topical application of vitamin E has been used in a wide variety of forms throughout history, ranging from the application of oils to the skin surface to the use of modern cosmetic formulations. Just as sebum provides a delivery mechanism for vitamin E to the stratum corneum, topical applications of vitamin E permeate the epidermis and dermis (14, 15). The rate of percutaneous vitamin E absorption and factors that influence its penetration are largely unknown in humans, with a large range of concentrations and times used in various studies. It is generally assumed that solutions with vitamin E concentrations as low as 0.1% can increase vitamin E levels in the skin (16). Interestingly, vitamin E levels in the dermis increase greatly after topical application, likely accumulating in the sebaceous glands (15). However, although it is increased after topical delivery, the concentration of vitamin E in the dermis is lower than in the stratum corneum. Skin supplied only with dietary vitamin E primarily contains alpha- and gamma-tocopherol (3, 7, 8); by contrast, skin supplied with synthetic vitamin E topically can contain a mixture of different tocopherols and/or tocotrienols (10, 15). In terms of penetration and absorption following topical application, tocotrienols and tocopherols accumulate in skin at varying rates, but the mechanisms governing these differences are unclear (15).
After topical application, vitamin E accumulates not only in cell membranes but also in the extracellular lipid matrix of the stratum corneum, where vitamin E contributes to antioxidant defenses. However, much of a topically applied dose of vitamin E alone will be destroyed in the skin following exposure to UV light (10). This suggests that although vitamin E is working as an antioxidant, it is unstable on its own and easily lost from the skin. Thus, improving the stability of topical applications with vitamin E is important. Products containing both vitamin C and vitamin E have shown greater efficacy in photoprotection than either antioxidant alone (see Photoprotection below).
The stability of topical vitamin E solutions may also be increased by the use of vitamin E conjugates. These vitamin E derivatives are usually commercially produced esters of tocopherol (although tocotrienol esters have been formulated) that are resistant to oxidation but can still penetrate the skin layers. Vitamin E conjugates, however, do not have antioxidant functions. To be effective, the molecule conjugated to vitamin E must be removed by enzymes within a cell. Since the stratum corneum contains metabolically inactive cells and the remaining layers of the epidermis and dermis may contain a large volume of extracellular proteins, it is unclear how efficiently ester conjugates are converted to “free” vitamin E in skin. Depending on the compound and the model system used, the effectiveness of these formulations can vary greatly (16-20), and studies often do not compare the application of vitamin E conjugates to the application of unmodified vitamin E molecules.
Because vitamin E can absorb UV light to produce free radicals (see Photoprotection below), there is the possibility that heavy sunlight exposure after topical application can cause skin reactions. However, concentrations of vitamin E between 0.1%-1.0% are generally considered safe and effective to increase vitamin E levels in the skin, but higher levels of alpha-tocopherol have been used with no apparent side effects (16). On the other hand, studies of dose-dependent vitamin E accumulation and effectiveness in skin protection are lacking. Some forms of vitamin E, especially ester conjugates, have led to adverse reactions in the skin, including allergic contact dermatitis and erythema. Although such reactions may be due to oxidation by-products, the emulsion creams used for topical delivery of compounds may also contribute to the observed effects (21).
Vitamin E deficiency may affect skin function, but there is little evidence from human studies. Vitamin E deficiency in rats has been reported to cause skin ulcerations (22) and changes in skin collagen cross-linking (23, 24), but the underlying cause of these effects is unknown.
Functions in Healthy Skin
The primary role of vitamin E in the skin is to prevent damage induced by free radicals and reactive oxygen species; therefore, the use of vitamin E in the prevention of UV-induced damage has been extensively studied. Although molecules in the vitamin E family can absorb light in the UVB spectrum, the “sunscreen” activity of vitamin E is considered limited since it cannot absorb UVA light or light in higher wavelengths of the UVB spectrum (25). Thus, the primary photoprotective effect of vitamin E is attributed to its role as a lipid-soluble antioxidant.
Many studies in cell culture models (in vitro studies) have found protective effects of vitamin E molecules on skin cells (26-28), but these models do not recreate the complex structure of skin tissues. Therefore, in vivo studies are needed.
Studies using orally administered vitamin E have reported mixed results on its photoprotective potential. An early study of vitamin E supplementation in hairless mice found no effect of dietary alpha-tocopherol acetate on UV-induced carcinogenesis (29). Three other mouse studies reported inhibition of UV-induced tumors in mice fed alpha-tocopherol acetate (30-32), but one of these studies utilized vitamin E doses that were toxic to animals when combined with the UV treatment (30). Another study in mice found a reduction of UV-induced DNA damage with dietary alpha-tocopherol acetate, but no effects on other free radical damage were observed in the skin (33). One human study reported that subjects taking 400 IU/day of alpha-tocopherol had reduced UV-induced lipid peroxidation in the skin but concluded there was no overall photoprotective effect (34). This was supported by another human study that found that 400 IU/day of alpha-tocopherol for six months provided no meaningful protection to skin (35). Furthermore, multiple human studies have shown no effect of vitamin E on the prevention or development of skin cancers (36, 37).
In contrast to oral supplementation with alpha tocopherol alone, multiple studies have found that the combination of vitamin C and vitamin E protects the skin against UV damage. Human subjects orally co-supplemented with vitamins C and E show increased Minimal Erythemal Dose (MED), a measure of photoprotection from UV light in skin (38, 39). The combination of the two vitamins was associated with lower amounts of DNA damage after UV exposure (40). Results of another study suggest a mixture of tocopherols and tocotrienols may be superior to alpha-tocopherol alone, as the mixture showed reduced sunburn reactions and tumor incidence after UV exposure in mice (41). However, further trials with dietary tocotrienol/tocopherol mixtures are needed in human subjects.
Topical application of vitamin E is generally effective for increasing photoprotection of the skin. In rodent models, the application of alpha-tocopherol or alpha-tocopherol acetate before UV exposure reduces UV-induced skin damage by reducing lipid peroxidation (33, 42-44), limiting DNA damage (33, 45-47), and reducing the many chemical and structural changes to skin after UV exposure (14, 48-50). Vitamin E topical applications have also been shown to reduce UV-induced tumor formation in multiple mouse studies (14, 31, 51) and to reduce the effects of photo-activated toxins in the skin (52-55). Topical application of vitamin E also reduces the effects of UV radiation when applied after the initial exposure. In mice, alpha-tocopherol acetate prevents some of the erythema, edema, skin swelling, and skin thickening if applied immediately after UV exposure (49, 50). A similar effect has been shown in rabbits, where applying alpha-tocopherol to skin immediately after UV increased the MED (56). While the greatest effect was seen when vitamin E was applied immediately after UV exposure, one study showed a significant effect of application eight hours after the insult (49). In human subjects, the use of vitamin E on skin lowers peroxidation of skin surface lipids (57), decreases erythema (58, 59), and limits immune cell activation after UV exposure (60).
Like oral supplementation with vitamin C and vitamin E, topical preparations with both vitamins have also been successful. Together, the application of these antioxidants to the skin of animals before UV exposure has been shown to decrease sunburned cells (61, 62), decrease DNA damage (61, 63), inhibit erythema (61, 64), and decrease skin pigmentation after UV exposure (64). Similar effects have been seen in human subjects (65-67).
While a majority of studies have found benefit of topical alpha-tocopherol, there is much less evidence for the activity of esters of vitamin E in photoprotection (57). As described above, vitamin E esters require cellular metabolism to produce “free” vitamin E. Thus, topical use of vitamin E esters may provide only limited benefit or may require a delay after administration to provide significant UV protection.
Vitamin E has been considered an anti-inflammatory agent in the skin, as several studies have supported its prevention of inflammatory damage after UV exposure. As mentioned above, topical vitamin E can reduce UV-induced skin swelling, skin thickness, erythema, and edema—all signs of skin inflammation. In cultured keratinocytes, alpha-tocopherol and gamma-tocotrienol have been shown to decrease inflammatory prostaglandin synthesis, interleukin production, and the induction of cyclooxygenase-2 (COX-2) and NADPH oxidase by UV light (68-70), as well as limit inflammatory responses to lipid hydroperoxide exposure (71). In mice, dietary gamma-tocotrienol suppresses UV-induced COX-2 expression in the skin (70). Furthermore, topical application of alpha-tocopherol acetate or a gamma-tocopherol derivative inhibited the induction of COX-2 and nitric oxide synthase (iNOS) following UV exposure (72). In vitro studies have shown similar anti-inflammatory effects of alpha- and gamma-tocopherol on immune cells (73-75).
Many of these anti-inflammatory effects of vitamin E supplementation have been reported in combination with its photoprotective effects, making it difficult to distinguish an anti-inflammatory action from an antioxidant action that would prevent inflammation from initially occurring. Despite these limitations, there are many reports of vitamin E being used successfully in chronic inflammatory skin conditions, either alone (76, 77) or in combination with vitamin C (78) or vitamin D (79), thus suggesting a true anti-inflammatory action.
As mentioned above, skin lesions have been reported in rats suffering from vitamin E deficiency, although their origin is unclear. Vitamin E levels decrease rapidly at the site of a cutaneous wound, along with other skin antioxidants, such as vitamin C or glutathione (80). Since skin antioxidants slowly increase during normal wound healing, these observations have stimulated additional studies on the effect of vitamin E on the wound healing process. However, no studies have demonstrated a positive effect of vitamin E supplementation on wound repair in normal skin. Studies have shown that alpha-tocopherol supplementation decreases wound closure time in diabetic mice, but no effects have been observed in normal mice (81, 82). Vitamin E increases the breaking strength of wounds pre-treated with ionizing radiation (83), but this is likely due to antioxidant functions at the wound site akin to a photoprotective effect. In contrast, intramuscular injection of alpha-tocopherol acetate in rats has been suggested to decrease collagen synthesis and inhibit wound repair (84).
In humans, studies with topical alpha-tocopherol have either found no effects on wound healing or appearance or have found negative effects on the appearance of scar tissue (85, 86). However, these studies are complicated by a high number of skin reactions to the vitamin E preparations, possibly due to uncontrolled formation of tocopherol radicals in the solutions used. Despite these results, vitamin E, along with zinc and vitamin C, is included in oral therapies for pressure ulcers (bed sores) and burns (87, 88).
There is limited information concerning the effects of vitamin E supplementation on photodamage, which is commonly observed as skin wrinkling. Although vitamin E can protect mice exposed to UV from excessive skin wrinkling, this is a photoprotective effect rather than treatment of pre-existing wrinkles. Other reports using vitamin E to treat photodamage or reduce wrinkles are poorly controlled studies or unpublished observations (89, 90). An analysis of the dietary intake of Japanese women showed no correlation between vitamin E consumption and skin wrinkling (91).
Vitamin E and oils containing tocopherols or tocotrienols have been reported to have moisturizing properties, but data supporting these roles are limited. Cross-sectional studies have shown no association between vitamin E consumption and skin hydration in healthy men and women (91, 92). However, two small studies have shown topical application of vitamin E can improve skin water-binding capacity after two to four weeks of use (93, 94). Long-term studies with topical vitamin E are needed to establish if these moisturizing effects can be sustained.
Environmental pollutants like ozone can decrease vitamin E levels in the skin (6, 11, 12) and lead to free radical damage that may compound the effects of UV exposure (12). Although not well studied, topical applications of vitamin E may reduce pollution-related free radical damage (11).
Vitamin E is an integral part of the skin’s antioxidant defenses, primarily providing protection against UV radiation and other free radicals that may come in contact with the epidermis. Oral supplementation with only vitamin E may not provide adequate protection for the skin, and co-supplementation of vitamin E and vitamin C may be warranted to effectively increase the photoprotection of skin through the diet. However, topical vitamin E seems to be an effective mechanism for both delivery to the skin and providing a photoprotective effect. Additional anti-inflammatory effects of topical vitamin E have been seen in the skin, although more studies are needed to determine if vitamin E primarily works as a free-radical scavenger or can have other effects on inflammatory signaling. Vitamin E is available commercially as a variety of synthetic derivatives, but the limited cellular metabolism in skin layers makes the use of such products problematic. Use of unesterified vitamin E, similar to that found in natural sources, has provided the most consistent data concerning its topical efficacy. The vitamin E family consists of eight different tocopherols and tocotrienols, and it will be important for future studies to determine if one or more of these molecules can have unique effects on skin function.
Source : Linus Pauling Institute
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VITAMIN E AND PROSTATE CANCER IN HEALTHY MEN
A paper published recently from the Selenium and Vitamin E Cancer Prevention Trial (SELECT) in the Journal of the American Medical Association (JAMA 306:1549-1556, 2011) concluded that "dietary supplementation with vitamin E significantly increased the risk of prostate cancer among healthy men." This alarming news spread fast, and many men are now wondering if it is prudent to take vitamin E supplements in light of this new information.
To date, two large randomized, placebo-controlled trials (RCTs) have been conducted in healthy men to investigate the effect of vitamin E supplementation on prostate cancer: The Physicians' Health Study (PHS) II and SELECT. PHS II (JAMA 301:52-62, 2009) followed 14,641 healthy men, aged 50 years and older, given 400 International Units (IU) of synthetic vitamin E every other day for eight years. In SELECT, 35,533 healthy men, aged 50 and older, received 400 IU of synthetic vitamin E every day for seven years. In both trials, there was no benefit of taking vitamin E supplements on prostate cancer risk. After a median time of 5.5 years in SELECT, vitamin E supplementation was discontinued, yet followup of the study participants continued for 1.5 years in order to document additional events. Unexpectedly, the SELECT updated analysis published recently in JAMA found a 17% increased risk of being diagnosed with prostate cancer in men who had taken the vitamin E supplement compared to those who had received placebo. No biological mechanism was proposed to explain the increased incidence of prostate cancer.
Why Did They Look at Vitamin E in the First Place? Vitamin E functions as a powerful, fat-soluble antioxidant in our cells and tissues. Antioxidants neutralize the effects of free radicals, highly reactive species that oxidize DNA, proteins, and lipids inside our cells, potentially causing damage and contributing to disease. In particular, oxidative DNA damage may cause mutations and, hence, increase the risk of certain cancers, including prostate cancer. Free-radical exposure is an unavoidable aspect of our lives, as these radicals are produced as a natural by-product of many biological processes, such as cellular respiration and inflammation, in addition to coming from our environment, particularly cigarette smoke. Antioxidants produced in the body and ingested in the diet are essential to reduce oxidative stress and counteract the potentially harmful effects of free radicals.
Some studies support a beneficial role for vitamin E in cancer and cardiovascular disease prevention. For example, the Women's Health Study (JAMA 294:56-65, 2005) followed 39,876 women who took 600 IU natural vitamin E every other day for ten years. The investigators found that supplemental vitamin E decreased cardiovascularrelated deaths by 24% but had no effect on cardiovascular Vitamin E and Prostate Cancer in Healthy Men events, overall cancer incidence, or cancer-related deaths. In general, studies have reported mixed results, and the impact of vitamin E supplementation on chronic disease risk remains controversial.
Why Are the Results Different? The Women's Health Study (WHS), PHS II, and SELECT are RCTs, also referred to as clinical trials or intervention studies. In RCTs, individuals are randomly assigned to either treatment (vitamin E in this case) or placebo, and the impact of the intervention on disease incidence is evaluated after several years.
The important issues that emerge from these RCTs are vitamin E dose (200-400 IU/day), vitamin E form (natural vs. synthetic), and population studied. Synthetic vitamin E (all-rac-alpha-tocopherol or dl-alpha-tocopherol) has half the bioactivity of naturally occurring vitamin E (RRR-alpha-tocopherol or d-alpha-tocopherol)—hence, the "effective dose" in PHS II and SELECT was only 100 and 200 IU/day, respectively, and 300 IU/day in WHS. Higher doses may be needed to effectively reduce oxidative stress. In one dose-response study, significant reductions in plasma F2-isoprostanes (a marker of oxidative stress) occurred only at daily doses of at least 1,600 IU of natural-source vitamin E. Notably, this dose is above the tolerable upper intake level (UL) of 1,500 IU/day set by the Food and Nutrition Board of the Institute of Medicine.
The fact that the vitamin E doses used in the RCTs appear insufficient to lower oxidative stress may explain the lack of benefit with respect to cancer risk. It remains unknown whether oxidative stress plays a causal role in prostate cancer. Furthermore, it remains unexplained why vitamin E supplementation in SELECT was associated with a 17% increased risk of prostate cancer, whereas vitamin E supplementation in PHS II and WHS was not associated with increased risk of any type of cancer in men and women, respectively.
Finally, the population studied in SELECT was healthy males consuming a well-balanced diet, most of whom likely were not vitamin E deficient or under increased oxidative stress. Unfortunately, neither baseline vitamin E levels in the study participants’ blood nor their oxidative stress status was assessed. In situations of stress, disease, or deficiency, meeting an increased demand with vitamin E supplementation may be warranted. However, in healthy people, vitamin E supplementation shows no added benefit on disease risk, as confirmed by the RCTs discussed here. For example, a study on the effect of supplemental vitamin E on cancer risk in 29,000 Finnish male smokers (the Alpha-Tocopherol Beta-Carotene [ATBC] trial) reported in 1998 that daily supplements of 75 IU/day of synthetic vitamin E for five to eight years were associated with a 32% and 41% reduction in prostate cancer diagnosis and mortality, respectively, compared to unsupplemented smokers. However, among other limitations, the ATBC study was not designed to assess prostate cancer incidence as a primary endpoint. Since oxidative stress was not measured in the study subjects, the mechanism for the possible protective effect of low-dose vitamin E remains obscure. Factors other than oxidative stress play an important role in the etiology of prostate cancer, such as endogenous hormones, race, age, and dietary fat intake.
Based on the lack of conclusive evidence for a benefit of vitamin E supplementation in cancer and cardiovascular disease prevention in generally healthy adults and the potential for harm in certain subpopulations, the Linus Pauling Institute has revised its "Rx for Health" and no longer includes a recommendation for supplemention with 200 IU/day of natural-source vitamin E.
What to Do? Vitamin E is an important micronutrient, and meeting daily recommendations is critical for optimum health. The Recommended Dietary Allowance (RDA) of vitamin E for adult men and women is 22.5 IU per day. Notably, more than 90% of individuals aged 2 years and older in the U.S. do not meet the daily requirement for vitamin E from food sources alone. Major sources of vitamin E in the American diet are vegetable oils, nuts, whole grains, and green leafy vegetables.
Taking all the issues discussed above into consideration, LPI recommends that generally healthy adults take a daily multivitamin/mineral supplement, which usually contains 30 IU of synthetic vitamin E, or 90% of the RDA.
Source : Linus Pauling Institute
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